“Unidad de Excelencia María de Maeztu”, funded by the MCIU and the AEI (DOI: 10.13039/501100011033). Ref: CEX2024-001431-M
“Unidad de Excelencia María de Maeztu”, funded by the MCIU and the AEI (DOI: 10.13039/501100011033). Ref: CEX2024-001431-M
Image legend: Genetic network of a human cell.
Jordi García-Ojalvo has received an ERC Synergy Grant for the CeLEARN project to investigate the concept that single cells can learn from their environment. The team, led by Dr. Aneta Koseska (Max Planck Institute), will study various model organisms to uncover universal mechanisms by which single cells create internal representations of the external world, similar to how the brain functions. Their ambitious goals include understanding how neurons learn to form connections during brain development and formulating a comprehensive theory of cellular learning. This interdisciplinary research aims to identify core internal representations and molecular mechanisms of single-cell learning, potentially leading to new therapies and technologies.
Project title: CeLEARN: Learning in Single Cells Through Dynamical Internal Representations. Funded under European Research Council (ERC). DOI 10.3030/101167121
Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
Reference: Ramos-Rodríguez, M., Subirana-Granés, M., et al. Implications of noncoding regulatory functions in the development of insulinomas. Cell Genomics (2024). DOI: 10.1016/j.xgen.2024.100604
Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remain poorly understood. Knockdown of ZMAT3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the PUMA and p21, the critical effectors of TRP53-mediated apoptosis and cell cycle arrest, respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma−/−p21−/−Zmat3−/− triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma−/−Zmat3−/− or p21−/−Zmat3−/−deficient mice. Interestingly, we observed that the triple knockout and Puma−/−Zmat3−/− double deficient animals succumbed to lymphoma, while p21−/−Zmat3−/− animals developed mainly solid cancers. This analysis suggests that, in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53-regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.
Reference: Brennan, M.S., Brinkmann, K., Romero Sola, G. et al. Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice. Cell Death Differ 31, 159–169 (2024). DOI: 10.1038/s41418-023-01250-w
Ecological variation and anthropogenic landscape modification have had key roles in the diversification and extinction of mammals in Madagascar. Lemurs represent a radiation with more than 100 species, constituting roughly one-fifth of the primate order. Almost all species of lemurs are threatened with extinction, but little is known about their genetic diversity and demographic history. Here, we analyse high-coverage genome-wide resequencing data from 162 unique individuals comprising 50 species of Lemuriformes, including multiple individuals from most species. Genomic diversity varies widely across the infraorder and yet is broadly consistent among individuals within species. We show widespread introgression in multiple genera and generally high levels of genomic diversity, likely resulting from allele sharing that occurred during periods of connectivity and fragmentation during climatic shifts. We find distinct patterns of demographic history in lemurs across the ecogeographic regions of Madagascar within the last million years. Within the past 2,000 years, lemurs underwent major declines in effective population size that corresponded to the timing of human population expansion in Madagascar. In multiple regions of the island, we identified chronological trajectories of inbreeding that are consistent across genera and species, suggesting localized effects of human activity. Our results show how the extraordinary diversity of these long-neglected, endangered primates has been influenced by ecological and anthropogenic factors.
Reference: Orkin, J.D., Kuderna, L.F.K., Hermosilla-Albala, N. et al. Ecological and anthropogenic effects on the genomic diversity of lemurs in Madagascar. Nat Ecol Evol 9, 42–56 (2025). DOI: 10.1038/s41559-024-02596-1
Prof. Ferran Sanz is the academic coordinator of the European VICT3R project, aiming to replace animal control groups in drug and chemical safety studies with virtual controls, in which Prof. Manuel Pastor and Prof. Olga Valverde also participate. These virtual controls will be created using existing data and AI, potentially reducing the number of animals used by up to 25%, contributing to the 3Rs of animal testing. The 3.5-year project, involving 33 public and private institutions, including 19 pharmaceutical companies and led academically by UPF and industrially by Bayer AG, builds on preliminary work from the eTRANSAFE project. VICT3R will refine the methodology for virtual controls, explore the use of AI for creating synthetic virtual animals when necessary, and aims to extend the concept to other toxicological and pharmacological studies. The project is part of the Innovative Health Initiative (IHI) and seeks to change the regulatory paradigm in preclinical safety testing.
Reference: VICT3R. Developing and implementing VIrtual Control groups To reducE animal use in toxicology Research. Funded under HORIZON.2.1.7 – Innovative Health Initiative. DOI: 10.3030/101172693
Pluripotent stem cells are being used to generate models of early embryogenesis that are promising for discovery and translational research. To be useful, these models require critical consideration of their level of efficiency and fidelity to natural embryos. Here we propose criteria with which to raise the standards of stem-cell-based embryo models of human embryogenesis.
Reference: Martínez Arias, A; Rivron, N; et al. Criteria for the standarization of stem-cell-based embryo models. Nature Cell Biology. September 2024. DOI: 10.1038/s41556-024-01492-x
The biotech company was chosen by the European Innovation Council (EIC) Accelerator program from among 969 European deep tech companies. This funding will enable Integra Therapeutics to launch its first gene therapy to treat a serious pediatric hepatic disease, among other activities
Microbial colonization of the neonatal gut involves maternal seeding, which is partially disrupted in cesarean-born infants and after intrapartum antibiotic prophylaxis. However, other physically close individuals could complement such seeding. To assess the role of both parents and induced seeding, we analyzed two longitudinal metagenomic datasets (health and early life microbiota [HELMi]: N = 74 infants, 398 samples, and SECFLOR: N = 7 infants, 35 samples) with cesarean-born infants who received maternal fecal microbiota transplantation (FMT). We found that the father constitutes a stable source of strains for the infant independently of the delivery mode, with the cumulative contribution becoming comparable to that of the mother after 1 year. Maternal FMT increased mother-infant strain sharing in cesarean-born infants, raising the average bacterial empirical growth rate while reducing pathogen colonization. Overall, our results indicate that maternal seeding is partly complemented by that of the father and support the potential of induced seeding to restore potential deviations in this process.
Reference: Dubois, L., Valles-Colomer, M. et al., Paternal and induced gut microbiota seeding complement mother-to-infant transmission, Cell Host & Microbe (2024). DOI: 10.1016/j.chom.2024.05.004
Rainforest hunter-gatherers from SE Asia are characterized by specific morphological features such as dark skin color, short stature, woolly hair, and the presence of steatopygia. Here, we first characterized signatures of adaptive natural selection around the CASR gene in several SE Asian rainforest groups and identified the R990G substitution as a putative adaptative variant for experimental follow-up. Next, we generated a knock-in mouse for this substitution and demonstrated that mice homozygous for the derived allele show greater body weight and fat accumulation, probably because of enhanced preadipocyte differentiation and lipolysis impairment. We speculate that such differential features in humans could have facilitated the survival of hunter-gatherer groups during periods of food scarcity. Moreover, the greater accumulation of fat could also promote an earlier sexual maturity by advancing puberty. In a hostile environment for survival, such as the rainforest, such a differential phenotype could have been highly adaptive while also contributing to the short stature of SE Asian hunter-gatherer populations.
Reference: Sinigaglia, B., Escudero, J., et al. Molecular Biology and Evolution; Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G. DOI: 10.1093/molbev/msae015
Image legend: A network was made from phenotype and multi-omics data from multiple sclerosis patients. The connections were made using Pearson correlation, and Boolean simulations were run on the networks. Paths were identified showing where information flows more strongly among scales.
Complex diseases such as Multiple Sclerosis (MS) cover a wide range of biological scales, from genes and proteins to cells and tissues, up to the full organism. In fact, any phenotype for an organism is dictated by the interplay among these scales. We conducted a multilayer network analysis and deep phenotyping with multi-omics data (genomics, phosphoproteomics, and cytomics), brain and retinal imaging, and clinical data, obtained from a multicenter prospective cohort of 328 patients and 90 healthy controls. Multilayer networks were constructed using mutual information for topological analysis, and Boolean simulations were constructed using Pearson correlation to identify paths within and among all layers. The path more commonly found from the Boolean simulations connects protein MK03 with total T cells, the thickness of the retinal nerve fiber layer (RNFL), and the walking speed. This path contains nodes involved in protein phosphorylation, glial cell differentiation, and regulation of stress-activated MAPK cascade, among others. Specific paths identified were subsequently analyzed by flow cytometry at the single-cell level. Combinations of several proteins (GSK3AB, HSBP1, or RS6) and immune cells (Th17, Th1 non-classic, CD8, CD8 Treg, CD56 neg, and B memory) were part of the paths explaining the clinical phenotype. The advantage of the path identified from the Boolean simulations is that it connects information about these known biological pathways with the layers at higher scales (retina damage and disability). Overall, the identified paths provide a means to connect the molecular aspects of MS with the overall phenotype.
Reference: Kennedy, K.E., Kerlero de Rosbo, N., et al. Multiscale networks in multiple sclerosis. PLoS Comput Biol. 2024 Feb 8;20(2):e1010980. DOI: 10.1371/journal.pcbi.1010980
Microorganisms can be equipped with synthetic genetic programs for the production of targeted therapeutic molecules. Cutibacterium acnes is the most abundant commensal of the human skin, making it an attractive chassis to create skin-delivered therapeutics. Here, we report the engineering of this bacterium to produce and secrete the therapeutic molecule neutrophil gelatinase-associated lipocalin, in vivo, for the modulation of cutaneous sebum production.
Reference: Knödlseder, N.J, et al., Delivery of a sebum modulator by an engineered skin microbe in mice. Nat. Biotechnol. 2024. Jan. DOI: 10.1038/s41587-023-02072-4
Background
North African human populations present a complex demographic scenario due to the presence of an autochthonous genetic component and population substructure, plus extensive gene flow from the Middle East, Europe, and sub-Saharan Africa.
Results
We conducted a comprehensive analysis of 364 genomes to construct detailed demographic models for the North African region, encompassing its two primary ethnic groups, the Arab and Amazigh populations. This was achieved through an Approximate Bayesian Computation with Deep Learning (ABC-DL) framework and a novel algorithm called Genetic Programming for Population Genetics (GP4PG). This innovative approach enabled us to effectively model intricate demographic scenarios, utilizing a subset of 16 whole genomes at > 30X coverage. The demographic model suggested by GP4PG exhibited a closer alignment with the observed data compared to the ABC-DL model. Both point to a back-to-Africa origin of North African individuals and a close relationship with Eurasian populations. Results support different origins for Amazigh and Arab populations, with Amazigh populations originating back in Epipaleolithic times, while GP4PG supports Arabization as the main source of Middle Eastern ancestry. The GP4PG model includes population substructure in surrounding populations (sub-Saharan Africa and the Middle East) with continuous decaying gene flow after population split. Contrary to ABC-DL, the best GP4PG model does not require pulses of admixture from surrounding populations into North Africa, pointing to soft splits as drivers of divergence in North Africa.
Conclusions
We have built a demographic model on North Africa that points to a back-to-Africa expansion and a differential origin between Arab and Amazigh populations.
Reference: Serradell, J.M., Lorenzo-Salazar, J.M., Flores, C. et al. Modelling the demographic history of human North African genomes points to a recent soft split divergence between populations. Genome Biol 25, 201 (2024). DOI: 10.1186/s13059-024-03341-4
Hematopoietic stem cells (HSCs) readily recover from acute stress, but persistent stress can reduce their viability and long-term potential. Here, we show that the nuclear factor of activated T cells 5 (NFAT5), a transcription modulator of inflammatory responses, protects the HSC pool under stress. NFAT5 restrains HSC differentiation to multipotent progenitors after bone marrow transplantation and bone marrow ablation with ionizing radiation or chemotherapy. Correspondingly, NFAT5-deficient HSCs fail to support long-term reconstitution of hematopoietic progenitors and mature blood cells after serial transplant. Evidence from competitive transplant assays shows that these defects are HSC intrinsic. NFAT5-deficient HSCs exhibit enhanced expression of type 1 interferon (IFN-1) response genes after transplant, and suppressing IFN-1 receptor prevents their exacerbated differentiation and cell death after reconstitution and improves long-term regeneration potential. Blockade of IFN-1 receptor also prevented the overdifferentiation of NFAT5-deficient HSCs after bone marrow ablation. These findings show that long-term IFN-1 responses to different hematopoietic stressors drive HSCs toward more differentiated progenitors, and that NFAT5 has an HSC-intrinsic role, limiting IFN-1 responses to preserve reconstitution potential. Our identification of cell-intrinsic mechanisms that strengthen the resistance of HSCs to stress could help to devise approaches to protect long-term stemness during the treatment of hematopoietic malignancies.
Reference: Traveset, L. et al. NFAT5 counters long-term IFN-1 responses in hematopoietic stem cells to preserve reconstitution potential. Blood Adv (2024) 8 (21): 5510–5526. DOI: 10.1182/bloodadvances.2023011306